Methods for treating type i diabetes with leptin and leptin agonists

Abstract

The present invention provides for methods of treating type I diabetes by inducing hyperleptinemia in subjects afflicted with type I diabetes. These methods can achieve normoglycemia and suppress hypergluconemia, and alleviate conditions associated with such, even in the absence of or at extremely low levels of adjunct insulin therapy, and without any appreciable increase in insulinogenesis.

1 . A method of treating type I diabetes comprising providing to a subject diagnosed with type I diabetes a therapeutically effective amount of (a) leptin, a leptin agonist, or a leptin derivative; and (b) no more than about 10% of a normal daily dosage of insulin supplementation. 
     
     
         2 . The method of  claim 1 , wherein said subject is a human. 
     
     
         3 . The method of  claim 1 , wherein said subject is a non-human animal. 
     
     
         4 . The method of  claim 1  or  claim 2 , wherein said non-human animal is a mouse or rat. 
     
     
         5 . The method of any one of  claims 1  through  4 , wherein said subject suffers from autoimmune type I diabetes. 
     
     
         6 . The method of any one of  claims 1  through  4 , wherein said subject suffers from chemically-induced type I diabetes. 
     
     
         7 . The method of any one of  claims 1  through  5 , wherein providing comprises administering leptin, a leptin agonist, or a leptin derivative to said subject. 
     
     
         8 . The method of any one of  claims 1  through  7 , wherein said leptin, leptin agonist, or leptin derivative comprises a polypeptide that has 83 percent or greater amino acid sequence identity to the amino acid sequence set out SEQ ID NO: 13, 14, or 15. 
     
     
         9 . The method of any one of  claims 1  through  8 , wherein said leptin agonist comprises metreleptin (SEQ ID NO: 13). 
     
     
         10 . The method of any one of  claims 1  through  9 , wherein providing comprises administering an expression cassette comprising a promoter operably linked to a leptin-encoding nucleic acid or a leptin agonist-encoding nucleic acid to said subject. 
     
     
         11 . The method of  claim 10 , wherein said promoter is a tissue specific or constitutive promoter. 
     
     
         12 . The method of  claim 10 , wherein said expression cassette is comprised within a lipid vehicle. 
     
     
         13 . The method of  claim 10 , wherein said expression cassette is comprised within a replicable expression construct. 
     
     
         14 . The method of  claim 13 , wherein said replicable expression construct is a non-viral construct. 
     
     
         15 . The method of  claim 13 , wherein said replicable expression construct is a viral construct. 
     
     
         16 . The method of  claim 15 , wherein said viral construct is an adenoviral construct, an adeno-associated viral construct, a pox-viral construct, a retroviral construct, or a herpesviral construct. 
     
     
         17 . The method any one of  claims 1  through  16 , wherein said one or more of the following diabetic symptoms are improved: excess gluconeogenesis, excess glycogenolysis, hyperglycemia, hyperglucagonemia, ketosis, diabetic ketoacidosis, hypertriglyceridemia, elevated plasma free fatty acid, weight loss, catabolic syndrome, terminal illness, hypertension, diabetic nephropathy, renal insufficiency, renal failure, hyperphagia, muscle wasting, diabetic neuropathy, diabetic retinopathy, or diabetic coma. 
     
     
         18 . The method of any one of  claims 1  through  17 , wherein the insulin daily dosage is 10-15%, inclusive, of the normal daily dosage. 
     
     
         19 . The method of any one of  claims 1  through  18 , wherein the insulin daily dosage is 5-10%, inclusive, of the normal daily dosage, inclusive. 
     
     
         20 . The method any one of  claims 1  through  19 , wherein the insulin dosage is less than 5% of the normal daily dosage. 
     
     
         21 . The method any one of  claims 1  through  20 , wherein the insulin dosage is between 0% and 5%, inclusive, of the normal daily dosage. 
     
     
         22 . The method of any one of  claims 1  through  21 , wherein no exogenous insulin is provided. 
     
     
         23 . The method of any one of  claims 1  through  22 , wherein said subject is essentially devoid of endogenous insulin. 
     
     
         24 . The method of any one of  claims 1  through  23 , wherein said subject is has uncontrolled type I diabetes. 
     
     
         25 . The method of any one of  claims 1  through  21 ,  23 , and  24 , wherein the insulin dosage is reduced following initiation of leptin or leptin agonist provision. 
     
     
         26 . The method of any one of  claims 1  through  25 , wherein providing comprises systemically administering to said subject said leptin, said leptin agonist, or said expression cassette. 
     
     
         27 . The method of any one of  claims 1  through  26 , wherein systemically administering comprises intravenous, intra-muscular, subcutaneous, intraperitoneal, transdermal or intra-arterial administration. 
     
     
         28 . The method of any one of  claims 1  through  27 , wherein providing comprises administering directly to a tissue of said subject leptin, said leptin agonist or said expression cassette. 
     
     
         29 . The method of  claim 28 , wherein said tissue is muscle or liver. 
     
     
         30 . The method of any one of  claims 1  through  29 , wherein providing comprises multiple administrations of said leptin, said leptin agonist or said expression cassette. 
     
     
         31 . The method of  claim 30 , wherein multiple administrations comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 200, 300, 400, 500 or more administrations. 
     
     
         32 . The method of  claim 30  or  claim 31 , wherein multiple administrations are separated by 6 hours, 12 hours, 1 day, 2 days, 3, days, 4, days, 5 days, 6 days, 1 week, 2 weeks, one month, two months, three months, 6 months or more. 
     
     
         33 . The method of any one of  claims 1  through  32 , wherein said providing achieves plasma leptin levels of greater than 10 ng/ml, 20 ng/ml, 50 ng/ml, 100 ng/ml, 200 ng/ml, 300 ng/ml or 400 ng/ml. 
     
     
         34 . The method of any one of  claims 1  through  33 , wherein said providing achieves a venous or capillary fasting blood glucose (FBG) levels of less than 200 mg/dl, less than 175 mg/dl, less than 150 mg/dl, less than 140 mg/dl, less than 130 mg/dl, less than 126 mg/dl, less than 120 mg/dl, or less than 115 mg/dl, less than 110 mg/dl, or less than 100 mg/dl. 
     
     
         35 . A method of restoring normoglycemia in a subject diagnosed with type I diabetes comprising inducing hyperleptinemia in said subject, wherein said inducing comprises the provision of a therapeutically effective amount of a leptin, a leptin agonist, or a leptin derivative, wherein said subject receives no more than about 10% of a normal daily dosage of insulin supplementation. 
     
     
         36 . The method of any one of  claims 1  through  35 , wherein said hyperleptinemia is characterized by plasma leptin levels of greater than 10 ng/ml, 20 ng/ml, 50 ng/ml, 100 ng/ml, 200 ng/ml, 300 ng/ml or 400 ng/ml. 
     
     
         37 . The method of any one of  claims 1  through  35 , wherein said method results in a venous or capillary fasting blood glucose (FBG) levels of less than 200 mg/dl, less than 175 mg/dl, less than 150 mg/dl, less than 140 mg/dl, less than 130 mg/dl, less than 126 mg/dl, less than 120 mg/dl, or less than 115 mg/dl, less than 110 mg/dl, or less than 100 mg/dl. 
     
     
         38 . A method of reducing, suppressing, attenuating, or inhibiting hyperglucogonemia or a condition associated with hyperglucogonemia in a subject diagnosed with type I diabetes comprising inducing hyperleptinemia in said subject, said inducing comprising providing a therapeutically effective amount of a leptin protein, a leptin agonist, or a leptin derivative, wherein said subject receives no more than about 10% of a normal daily dosage of insulin supplementation. 
     
     
         39 . The method of any of  claim 38 , wherein said hyperleptinemia is characterized by plasma leptin levels of greater than 10 ng/ml, 20 ng/ml, 50 ng/ml, 100 ng/ml, 200 ng/ml, 300 ng/ml or 400 ng/ml. 
     
     
         40 . The method of  claim 38  or  39 , wherein said method results in a venous or capillary fasting blood glucose (FBG) levels of less than 200 mg/dl, less than 175 mg/dl, less than 150 mg/dl, less than 140 mg/dl, less than 130 mg/dl, less than 126 mg/dl, less than 120 mg/dl, or less than 115 mg/dl, less than 110 mg/dl, or less than 100 mg/dl. 
     
     
         41 . A method of reducing HbAlc in a subject having type I diabetes comprising inducing hyperleptinemia in said subject, said inducing comprising providing a therapeutically effective amount of a leptin protein, a leptin agonist, or a leptin derivative, wherein said subject receives no more than about 10% of a normal daily dosage of insulin supplementation. 
     
     
         42 . The method of any of  claim 41 , wherein said hyperleptinemia is characterized by plasma leptin levels of greater than 10 ng/ml, 20 ng/ml, 50 ng/ml, 100 ng/ml, 200 ng/ml, 300 ng/ml or 400 ng/ml. 
     
     
         43 . The method of  claim 41  or  42 , wherein said method results in a venous or capillary fasting blood glucose (FBG) levels of less than 200 mg/dl, less than 175 mg/dl, less than 150 mg/dl, less than 140 mg/dl, less than 130 mg/dl, less than 126 mg/dl, less than 120 mg/dl, or less than 115 mg/dl, less than 110 mg/dl, or less than 100 mg/dl. 
     
     
         44 . The method of any one of  claims 1  through  43 , wherein said therapeutically effective amount of said leptin protein, leptin agonist, or leptin derivative comprises: about 1 μg per day; about 5 μg per day; about 10 μg per day; about 50 μg per day to about 100 μg per day; about 500 μg per day; about 1 mg per day; about 5 mg per day; about 10 mg per day; about 50 mg per day; or about 100 mg per day. 
     
     
         45 . The method of any one of  claims 1  through  44 , wherein said therapeutically effective amount of said leptin protein, leptin agonist, or leptin derivative comprises a daily dosage of from about 0.01 mg/kg to about 100 mg/kg; from about 0.01 mg/kg to about 80 mg/kg; from about 0.01 mg/kg to about 70 mg/kg; from about 0.01 mg/kg to about 60 mg/kg; from about 0.01 mg/kg to about 50 mg/kg; from about 0.01 mg/kg to about 40 mg/kg; from about 0.01 mg/kg to about 30 mg/kg; from about 0.01 mg/kg to about 25 mg/kg; from about 0.01 mg/kg to about 20 mg/kg; from about 0.01 mg/kg to about 15 mg/kg; from about 0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 3 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.3 mg/kg from about 100 mg/kg to about 90 mg/kg; from about 100 mg/kg to about 80 mg/kg; from about 100 mg/kg to about 70 mg/kg; from about 100 mg/kg to about 60 mg/kg; from about 100 mg/kg to about 50 mg/kg; from about 100 mg/kg to about 40 mg/kg; from about 85 mg/kg to about 10 mg/kg; from about 75 mg/kg to about 20 mg/kg; from about 65 mg/kg to about 30 mg/kg; from about 55 mg/kg to about 35 mg/kg; from about 55 mg/kg to about 45 mg/kg; or from about 0.01 mg/kg to about 20 mg/kg. 
     
     
         46 . The method of any one of  claims 1  through  45 , wherein said therapeutically effective amount is provided by injection of a single dose or in divided doses. 
     
     
         47 . The method of any one of  claims 1  through  45 , wherein said therapeutically effective amount is provided by continuous infusion at an infusion rate of: from about 0.01/pmol/kg/min to about 10 pmol/kg/min. 
     
     
         50 . A method of treating type1 diabetes comprising providing to a subject diagnosed with type I diabetes a therapeutically effective amount of (a) leptin, a leptin agonist, or a leptin derivative; wherein said subject is essentially devoid of endogenous insulin. 
     
     
         51 . A method of treating type I diabetes comprising providing to a subject diagnosed with type I diabetes a therapeutically effective amount of (a) leptin, a leptin agonist, or a leptin derivative; in the absence of exogenous insulin. 
     
     
         52 . The method of  claim 51  or  claim 52 , wherein said subject is a human. 
     
     
         53 . The method of  claim 51  or  claim 52 , wherein said subject is a non-human animal. 
     
     
         54 . The method of any one of  claim 51  through  53 , wherein said non-human animal is a mouse or rat. 
     
     
         55 . The method of any one of  claims 51  through  54 , wherein said subject suffers from autoimmune type I diabetes. 
     
     
         56 . The method of any one of  claims 51  through  54 , wherein said subject suffers from chemically-induced type I diabetes. 
     
     
         57 . The method of any one of  claims 51  through  56 , wherein providing comprises administering leptin, a leptin agonist, or a leptin derivative to said subject. 
     
     
         58 . The method of any one of  claims 51  through  57 , wherein said leptin, leptin agonist, or leptin derivative comprises a polypeptide that has 83 percent or greater amino acid sequence identity to the amino acid sequence set out SEQ ID NO: 13, 14, or 15. 
     
     
         59 . The method of any one of  claims 51  through  88 , wherein said leptin agonist comprises metreleptin (SEQ ID NO: 13). 
     
     
         60 . A method of reducing, suppressing, attenuating, or inhibiting hyperglucogonemia or a condition associated with hyperglucogonemia in a subject diagnosed with type I diabetes comprising inducing hyperleptinemia in said subject, said inducing comprising providing a therapeutically effective amount of a leptin protein, a leptin agonist, or a leptin derivative, wherein said subject is essentially devoid of endogenous insulin. 
     
     
         61 . A method of reducing, suppressing, attenuating, or inhibiting hyperglucogonemia or a condition associated with hyperglucogonemia in a subject diagnosed with type I diabetes comprising inducing hyperleptinemia in said subject, said inducing comprising providing a therapeutically effective amount of a leptin protein, a leptin agonist, or a leptin derivative, in the absence of exogenous insulin. 
     
     
         62 . The method of any one of  claim 60  or  claim 61 , wherein said hyperleptinemia is characterized by plasma leptin levels of greater than 10 ng/ml, 20 ng/ml, 50 ng/ml, 100 ng/ml, 200 ng/ml, 300 ng/ml or 400 ng/ml. 
     
     
         63 . The method of any one of  claims 60  through  62 , wherein said hyperglucogonemia or a condition associated with hyperglucogonemia comprises at least one of the following: excess gluconeogenesis, excess glycogenolysis, hyperglycemia, hyperglucagonemia, ketosis, diabetic ketoacidosis, hypertriglyceridemia, elevated plasma free fatty acid, weight loss, catabolic syndrome, terminal illness, hypertension, diabetic nephropathy, renal insufficiency, renal failure, hyperphagia, muscle wasting, diabetic neuropathy, diabetic retinopathy, or diabetic coma 
     
     
         64 . The method of any one of  claims 60  through  63 , wherein said subject is a human. 
     
     
         65 . The method of any one of  claims 60  through  63 , wherein said subject is a non-human animal. 
     
     
         66 . The method of  claim 65 , wherein said non-human animal is a mouse or rat. 
     
     
         67 . The method of any one of  claims 60  through  66 , wherein said subject suffers from autoimmune type I diabetes. 
     
     
         68 . The method of any one of  claims 60  through  66 , wherein said subject suffers from chemically-induced type I diabetes. 
     
     
         69 . The method of any one of  claims 60  through  68 , wherein providing comprises administering leptin, a leptin agonist, or a leptin derivative to said subject. 
     
     
         70 . The method of any one of  claims 60  through  69 , wherein said leptin, leptin agonist, or leptin derivative comprises a polypeptide that has 83 percent or greater amino acid sequence identity to the amino acid sequence set out SEQ ID NO: 13, 14, or 15. 
     
     
         71 . The method of any one of  claims 60  through  70 , wherein said leptin agonist comprises metreleptin (SEQ ID NO: 13).